The present invention relates to a method of dietary control which reduces the effects of infection as well as minimizing the effects of subsequent infection in at risk animals, particularly human patients. A dietary supplement useful in the method of the invention is also disclosed.
Animals can be infected by many agents which break down the natural defenses and cause illness. These agents include bacteria, viruses, parasites, and fungi. While a great number of drugs have been developed to combat these infectious agents, the primary defense is the body's own immune system. The effectiveness of the body's defensive system against infection depends on the level of certain chemicals, e.g., prostaglandins, in the blood and cell membranes. These chemicals are synthesized from precursor molecules, e.g., fatty acids, obtained in the diet. In fact, some antiinfection drugs work by modifying the levels of synthesis of these molecules.
The amount and family of fatty acids in the diet is one of the keys to nutrition. There are three major families of polyunsaturated fatty acids: .omega.3, .omega.6 and .omega.9. The names are based on the location of the closest double bond to the methyl end of the fatty acid; that is, if the closest double bond is between the third and fourth carbon atoms from the methyl group, the molecule is a .omega.3 fatty acid while if the double bond is between the sixth and seventh carbons, it is classified as a .omega.6 fatty acid. Mammals can desaturate or elongate fatty acid chains but cannot interconvert fatty acids from one family to another. The most significant fatty acids are those which have been desaturated and elongated to the twenty carbon length. The .omega.9 fatty acids are elongated to form eicosatrienoic acids (C20:3.omega.9), the .omega.6 fatty acids form arachidonic acid (C20:4.omega.6), and the .omega.3 fatty acids form eicosapentaenoic acid (C20:5.omega.3) or docosahexaenoic acid (C22:6.omega.3). The notation (Chd --:.sub.-- .omega..sub.--) gives the number of carbons in the chain, the number of double bonds and the class of the fatty acid, respectively.
Most people in industrialized nations obtain a high proportion of their fatty acids from meat fats and vegetable oils. These fatty acid sources are high in .omega.6 fatty acids and low in .omega.3 fatty acids. Therefore, arachidonic acid is the predominant twenty carbon desaturated and elongated fatty acid in the plasma and membranes of these people. In countries where fish oil, which contains a high proportion of .omega.3 fatty acids, is the predominant fatty acid source, eicosapentaenoic acid is the major desaturated fatty acid found in the plasma and membranes.
Part of the significance of the twenty carbon fatty acids is their ability to act as substrates in the prostanoid synthesis pathway which forms prostaglandins from fatty acids. The first enzyme in this pathway is cyclo-oxygenase whose primary substrate in mammals is arachidonic acid. In the platelets, arachidonic acid is modified by the enzymes of the pathway to form thromboxane A.sub.2, a potent platelet aggregator and vasoconstrictor. In endothelial cells, arachidonic acid forms prostacyclin I.sub.2, a vasodilator and platelet antiaggregator. Both thromboxane A.sub.2 and prostacyclin I.sub.2 are prostaglandins of the "2" series.
However, the enzyme cyclo-oxygenase can also use eicosapentaenoic acid as a substrate. In the platelets, eicosapentaenoic acid is formed into thromboxane A.sub.3. Thromboxane A.sub.3 is a weak vasoconstrictor but unlike thromboxane A.sub.2, it will not aggregate platelets. In endothelial cells, prostacylin I.sub.3, which has vasodilatory and platelet antiaggregating properties similar to prostacyclin I.sub.2, is formed from eicosapentaenoic acid. Thromboxane A.sub.3 and prostacyclin I.sub.2 are prostaglandins of the "3" series. If docosahexaenoic acid is formed upon chain elongation and desaturation, or since it is present in fish oils, it also can be used as a substrate for cyclo-oxygenase. This also decreases the level of series "2" prostaglandin formation.
The fact that both .omega.3 and .omega.6 fatty acids can act as substrates for the prostanoid synthesis pathway led to the theory that dietary manipulation could modify the levels of type 2 and type 3 prostaglandins in the platelets and cell membranes. According to this theory, the availability of .omega.3 fatty acids in the diet would cause a decrease in the level of type 2 prostaglandins in the plasma and membranes through competitive inhibition for the enzymes which normally use .omega.6 fatty acids as substrates. In one experiment on dietary manipulation, Sanders, Vickers and Haines, Clin. Sci. 61:317-324 (1981), investigated the effect on blood lipids and hemostasis in healthy young men by supplementing their diet with cod liver oil, an oil rich in .omega.3 fatty acids. These researchers found that the ratio of .omega.3 to .omega.6 fatty acids and resulting products was increased in the platelets and erythrocyte phosphoglycerides by this diet modification.
In a series of papers by Dyerberg et al, e.g., Am. J. Clin. Nutr 28:958-966 (1975), Lancet 2:433-435 (1979), and Am. J. Clin. Nutr. 33:2657-2661 (1970), the effects of diet high in .omega.3 fatty acids on heart disease were studied. The Greenland Eskimos, who have a low meat and high fish oil diet, were the test subjects. Since meat is high in .omega.6 fatty acids while fish oils have significant quantities of .omega.3 fatty acids, these studies provided a comparison between high .omega.6 and high .omega.3 diets. The Eskimos with the high .omega.3 fatty acid diets had significantly lower incidence of heart disease than Eskimos who had high .omega.6 fatty acid diets. The latter group were primarily Eskimos who had moved to Denmark and changed their diet to have a substantial proportion of .omega.6 fatty acids. These experiments showed that dietary manipulation could change the susceptibility to heart disease.
Some hospitalized patients, particularly critically ill patients, receive total parenteral nutrition. Since most patients receiving parenteral nutritional systems have a high risk of infection, a diet which minimizes the risk of infection would be a substantial benefit to this class of patients. Parenteral nutrition diets include a source of fatty acids since fatty acids are necessary for adequate biochemical functioning. However, standard parenteral diets use fatty acids derived primarily from soybean or safflower oil which as with most plant oils, are high in .omega.6 fatty acids but have little or no .omega.3 fatty acid content. While some .omega.6 fatty acids are essential to good health, somewhere between 2 and 4 percent of the total calorie content is all that is necessary. Conventional parenteral nutrition diets supply 10-15 percent, occasionally as high as 50 percent, of the calorie content as the .omega.6 fatty acids, a clear excess.
Lowering .omega.6 fatty acids may lead to an increase in platelet thromboxane A.sub.3 levels. One theory for the decreased heart disease among eskimoes is that the platelets are not as "sticky" if the thromboxane A.sub.2 levels are lowered. Since the production of thromboxane A.sub.3 is normally at the expense of thromboxane A.sub.2, a diet which lowers the .omega.6 fatty acid levels might lead to a decrease in heart disease.
Cook, Wise and Halushka, J. Clin. Invest. 65:227 (1980) investigated the thromboxane A.sub.2 levels in rats challenged with endotoxin. They found endotoxin shock increases thromboxane A.sub.2 levels in the platelets. Rats treated with imidazole (a thromboxane synthetase inhibitor), indomethacin (a fatty acid cyclo-oxygenase inhibitor), or those animals with essential fatty acid deficiency (.omega.6 fatty acid deficiency) had higher survival rates to endotoxin shock than did normal rats. All of the groups of animals with higher survival rates exhibited lower thromboxane A.sub.2 levels.
Accordingly, an object of the invention is to provide a method of minimizing the effects of infection and minimizing the effects of subsequent infection in at risk animals, particularly humans, by administering a diet which promotes resistance to infection without interfering with essential bodily processes. Another object of the invention is to provide a dietary supplement which provides sufficient nutrition in animals while reducing the risk of infection. A further object of the invention is to provide a method of treating patients, primarily patients having high risk of infection, with a dietary supplement which provides essential fatty acids while assisting in resistance to infection. These and other objects and features of the invention will be apparent from the following description.